Process for preparing triazolobenzodiazepines

ABSTRACT

A process for preparing triazolobenzodiazepines via the condensation of the corresponding 2-hydrazinobenzodiazepine with an aliphatic dione, followed by cyclization of the open intermediate, is described. The products obtainable by this process are known compounds and are useful as sedative and tranquilizing agents.

United States Patent [191 Fryer et al.

[ Aug. 26, 1975 PROCESS FOR PREPARING TRIAZOLOBENZODIAZEPINES [75] Inventors: Rodney Ian Fryer, North Caldwell;

Armin Walser, West Caldwell, both of NJ.

[73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: Aug. 28, 1974 [21] Appl. No.: 501,312

Related U.S. Application Data [63] Continuation-impart of Ser. No. 408,245, Oct. 19,

1973, Pat No. 3,864,328.

[52] U.S. Cl 260/308 R [51] Int. Cl. C07D 487/04 [58] Field of Search 260/308 R [56] References Cited OTHER PUBLICATIONS Potts, Chem. Reviews, Vol. 61, Pages (1961).

Elderfield, Heterocyclio Compounds, Vol. 7, (New York, 1961), pages 435-438.

Primary ExaminerAlton D. Rollins Attorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; Frank P. Hoffman [57] 7 ABSTRACT 1 Claim, N0 Drawings PROCESS FOR PREPARING TRIAZOLOBENZODIAZEPINES This is a continuation-in-part of Ser. No. 408.245. filed Oct. I9. 1973. now US. Pat. No. 3.864.328.

DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing known and pharmacologically valuable triazolobenzodiazepines. More particularly the present invention is concerned with the preparation of 6-phenyl-4I-I-S- triazolo [4.3-al[-l .4-1 benzodiazepines. The end products obtained in employing the inventive process are useful as sedative and tranquilizing agents.

Following the process of the present invention. one can prepare triazolohenzodiazepines of the formula R is selected from the group consisting of hydrogen, halogen. nitro, trifluoromethyl, lower alkyl and lower alkoxy; R signifies hydrogen or lower alkyl; R: signifies hydrogen or lower alkyl; and R signifies hydrogen or halogen.

As used herein. the term lower alkyl" either alone or in combination refers to straight and branched chain hydrocarbon groups containing from I to 7, preferably from 1-4. carbon atoms. such as. for example, methyl, ethyl, propyl. isopropyl. isobutyl. butyl and the like. The term halogen refers to all four forms thereof. i.e.. bromine. chlorine, fluorine and iodine. The term lower alkoxy designates straight or branched chain saturated hydrocarbonoxy groups containing from I to 7 carbon atoms, preferably from I to 4 carbon atoms such as methoxy, ethoxy, propoxy and the like.

In following the novel process of the present invention. the known and useful compounds of formula I above are prepared by condensing a 2- hydrazinobenzodiazepine of the formula wherein A. R and R are as described above with an aliphatic dione. followed by cyclization of the resulting open hydrazone intermediate.

In a preferred aspect of the present invention. R in the starting material of formula II is halogen or nitro, R is hydrogen. A is the group and R is located in the ortho position of the S-phenyl ring; so that by following the novel process of the present invention there is obtained a compound of the for-' mula wherein R signifies halogen or nitro and R and R are as described above.

In another preferred aspect. if the R substituent is lower alkyl. it is preferably a methyl group; if the R substituent is halogen, chlorine is preferred. while if R; is halogen, chlorine or fluorine are preferred.

As discussed above, the compounds of formula I above are prepared by first condensing a 2- hydrazinobenzodiazepine of formula II above with an aliphatic dione of the formula III wherein R and R are individually hydrogen or lower alkyl, at least one of R or R being lower alkyl.

vThe reaction between the benzodiazepine of formula II and the dione of formula III results in a tautomeric mixture of the open hydrazone intermediate of the formula R l N\ M H wherein R. R R R,-, and A are as described above.

The first stage of the process described above, i.e.,

the treatment with an aliphatic dione of the compound of formula ll is effected in the presence of an inert organic solvent. Among the many inert organic solvents suitable for the purposes of the present invention. there can be included lower alkanols such as methanol. ethanol, and the like; others such as diethyl ether. dimethylformamide. dimethylsulfoxide, All that is required of the solvent in this step and in the step described hereinafter is that the starting material be soluble therein and that it not interfere with the ensuing reaction.

While temperature and pressure are not critical to the successful treatment of a compound of the formula ll with an aliphatic dione, it is preferred to operate at a temperature range of from about to about 70; most preferably about room temperature.

It is expected that the ketone of formula IV and its enol form of formula [Va exist in equilibrium in the reaction medium in which the preparation thereof is effected. In the subsequent cyclization step described hereinafter. it is to be understood that a compound of formula IV and/or its enol form of formula [Va is the intermediate employed in the cyclization to the desired compound of formula I above.

It is obvious from the course of the reaction between the compounds of formula ll and Ill above that upon cyclization of the tautomeric mixture of the compounds of formulae IV and lVa, the substituent that will be present in the l-position of the product of formula I will correspond to the R substituent in the formula III compound. Thus, if it is desired to prepare a compound of formula I unsubstituted in the 1-position, that is wherein R signifies hydrogen. then the appropriate benzodiazepine of formula II is reacted with an a-formyl ketone, that is a compound of formula III wherein R signifies hydrogen and R signifies lower alkyl. This reagent can also exist in the'enol form as shown by the following equilibrium equation:

wherein R,-, signifies lower alkyl. Since the formyl portion of the a-formyl ketone is the more reactive site in the molecule, it is this site that will react with the hydrazino group, resulting, upon cyclization, in a compound of formula 1 herein R is hydrogen. If the R and R groups in the compound of formula III are the same lower alkyl groups, then the condensation and cyclization reactions will result in a single triazolobenzodiazepine product. For example, if acetylacetone is employed as the dione of formula ii], there is obtained a compound of formula I wherein R signifies methyl. lf 3,5-heptane dione is used, the resulting triazolo derivative bears an ethyl group as the R substituent. In the case where R and R are different lower alkyl groups, for example where 2.4-hexanedione is employed, the process will result in a mixture of two triazolo derivatives bearing different lower alkyl groups as the R, substitue-nt. These compounds can, of course. be separated following conventional techniques.

The second step of the process herein defined, the cyclization of the open hydrazone intermediate which results from the treatment of a compound of the formula ll with an aliphatic dione is effected in the presence of an inert organic solvent whichis suitable for the purposes of the invention as described above. Suitable inert organic solvents may be represented by lower alkanols such as methanol, ethanol. and the like; aromatic hydrocarbons such as xylene, benzene, toluene, and the like.

While temperature is not critical to a successful performance of this second stage, it is preferred to effect the reaction at elevated temperatures, e.g., from about 30 to about the reflux temperature of the reaction medium; most prefer-ably at about reflux temperature.

It should be understood that in preparing the triazolobenzodiazepine end product, it is not necessary to isolate the hydrazone intermediate. If the reaction mixture of the condensation is heated, preferably at reflux, cyclization will occur in situ.

The starting materials of formula II above are known compounds. The intermediates of formula ]V and lVa are novel and as such form a part of the present invention.

The following examples are illustrative but not limitative of the present invention. All temperatures are given in degrees centigrade.

EXAMPLE l Preparation of 7-Chloro-2-[2-( 3-hydroxyl -methyl-2- butenylidene)hydrazo1-S-phenyl-3H-l,4- benzodiazepine 4-oxide.

A mixture of 15g (0.05 mol) of 7-chloro-2- hydrazino-5-phenyl-3H-l ,4-benzodiazepine 4-oxide, 20g (0.2 mol) of acetylacetone and 400 ml of methanol was warmed until solution was complete. After sitting over night at room temperature, condensation resulted in a tautomeric mixture of 7-chloro-2-[2-( 3-hydroxyl methyl-Z-butenylidene )hydrazo l-5-phenyl-3H-l ,4- benzodiazepine 4-oxide and 7-chloro-2-[2-( l-methyl- 3-oxo-butylidene )hydrazo] 5-phenyl-3H-l ,4- benzodiazepine 4-oxide. The solvent was then removed under reduced pressure and the residue was crystallized from ether to give a yellow product. For analysis the product was purified by chromatography over silica gel using methylene chloride/ethylacetate, 1:1 (v/v). Crystallization from methylene chloride/ether gave the above named product as pale yellow crystals with mp l-l 86.

EXAMPLE 2 Preparation of 8 Chlorol -methyl-6-phenyl-4H-s-triazolo[4,5-a][ 1,4] benzodiazepine 5-oxide.

A mixture of 3,8g (0.01 mol) of 7-chloro-2-[2-(3- hydroxyl -methyl-2-butenylidene )hydrazo]-5-phenyl- 3H-l,4-benzodiazepine 4-oxide and ml of xylene was refluxed for 16 hrs while 50 ml ofsolvent was distilled and collected in a Dean-Stark trap. The crystalline material separated upon cooling and collected to yield the above-named product with mp 278-280 dec.

EXAMPLE 3 Preparation of 8-Chlorol -methyl-6-phenyl-4H-s-triazolo[4,5-a][ 1,4]

I benzodiazepine 5-oxide.

A mixture of 3.8g (0.01 mol) of 7-chloro-2-[2-(3- hydroxyl -methyl-2-butcn vlitlene )hydrazo1-5-phenyl- 3H-l.4-benzodiaxepinc 4-oxide. 100 ml of n-butanol and 1 ml of triethylaminc was refluxed for 16 hrs. The crystals separated upon cooling and were collected to yield the above-named product with mp 278282 dec.

EXAMPLE 4 Preparation of 7-Ch|oro-2-[ 2-( B-hydroxyl -methyl-2- butenylidene )hydrazo I-S-phenyl-BH-l ,4-

benzodiazepine.

EXAMPLE 5 Preparation of 8-Chlorol -methyl-6-phenyl-4H-s-triazolo [4,5-a][ 1.4] benzodiazepine.

A mixture of 0.37 g of 7-chloro-2-[2-(3-hydroxy-lmethyl-Z-hutenylidene )hydrazo]-5-phenyl-3H- l .4- benzodiazepine. 0.3 ml of triethylamine and ml of n-butanol was refluxed for 16 hrs. The solvents were removed under reduced pressure and the residue was crystallized from methylene chloride/ethylacetate/ethcr to yield the above named product with mp. 225226.

EXAMPLE 6 Preparation of S-Chlorol -methyl-6-phenyl-4H-s-triazolo[4,5-a][ 1,41 benzodiazepine A mixture of 2.0 g of 7-chlor0-2-hydrazino-5-phenyl- 3H-l.4-benzodiazepine, 20 ml of n-butanol, 0.3 ml of triethylamine and 2 ml of acetylacetone was refluxed for 16 hours. The solvents were removed under reduced pressure and the residue was crystallized from methylene chloride/ethylacetate/ether to yield the above-named product. m.p. 225227.

We claim:

1. A process for the preparation of a triazolobenzodiazepine of the formula wherein A is selected from the group consisting of and R is selected from the group consisting of hydrogen, halogen. nitro. trifluoromethyl, lower alkyl and lower alkoxy; R signifies hydrogen or lower alkyl; R: signifies hydrogen or lower alkyl; and R signifies hydrogen or halogen which comprises:

a. condensing in the presence of an inert organic solvent a compound of the formula wherein R. R and A are as described above with a dione of the formula wherein R and R are individually hydrogen or lower alkyl. at least one of R or R being lower alkyl to yield a tautomeric mixture comprising compounds of the formula wherein R, R R R and A are as described above; b. cyclizing the so-obtained condensation product.

with or without isolation, by the thermal treatment thereof to yield the triazolobenzodiazepine end product.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 2 3,901,907

DATED I October 3, 1975 lNVEN 1 Rodney Ian Fryer and Armin Walser It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 6, line 41 of Letters Patent claim 1 should be lOI Cl) R4 "*C-"'*CHI2 --C-'*R5 Signed and Scaled this sixteenth' Day Of December 1975 [SEAL] Attest:

RUTH C. MASON c. MARSHALL DANN Al esling ff l'tt" Commissioner of Parents and Trademarks 

1. A PROCESS FOR THE PREPARATION OF A TRIAZOLOBENZODIAZEPIN OF THE FORMULA 